Lanthanide-Based T_2ex and CEST Complexes Provide Insights into the Design of pH Sensitive MRI Agents

The CEST and T₁/T₂ relaxation properties of a series of Eu³⁺ and Dy³⁺ DOTA-tetraamide complexes with four appended primary amine groups are measured as a function of pH. The CEST signals in the Eu³⁺ complexes show a strong CEST signal after the pH was reduced from 8 to 5. The opposite trend was observed for the Dy³⁺ complexes where the r_2ex of bulk water protons increased dramatically from ca. 1.5 mm⁻¹ s⁻¹ to 13 mm⁻¹ s⁻¹ between pH 5 and 9 while r₁ remained unchanged. A fit of the CEST data (Eu³⁺ complexes) to Bloch theory and the T_2ex data (Dy³⁺ complexes) to Swift–Connick theory provided the proton-exchange rates as a function of pH. These data showed that the four amine groups contribute significantly to proton-catalyzed exchange of the Ln³⁺-bound water protons even though their pK_a’s are much higher than the observed CEST or T_2ex effects. This demonstrated the utility of using appended acidic/basic groups to catalyze prototropic exchange for imaging tissue pH by MRI.